The overall objective of this proposal is to determine the molecular signals for plasticity in central nervous system that change the reflex control of breathing during chronic hypoxia. This research is significant because it addresses a fundamental but unanswered question in pulmonary medicine: Do changes in the control of breathing occur with chronic hypoxemia from lung disease and, if so, are there individual differences and how do they affect the progression of disease? We have developed methods to study the basic problem at the molecular level in conscious behaving laboratory rodent models, and results from these experiments have produced hypotheses that we have been able to test in humans. Specifically, we have shown that the common anti-inflammatory drug ibuprofen blocks time dependent increases in ventilation and ventilatory sensitivity to oxygen during chronic hypoxia in rodents and in healthy humans. This poses exciting new questions about the role of inflammatory signals for healthy and normal plasticity in the chemoreflex control of breathing. For example, inflammation is necessary for ventilatory acclimatization to hypoxia, which is beneficial by increasing O2 supply when O2 availability is decreased for long periods of time, but inflammation with bacterial infection can decrease ventilation and O2 supply, which exacerbates conditions. Also, we have preliminary data showing the transcription factor hypoxia inducible factor-1? (HIF-1?) is necessary in brainstem respiratory centers for normal ventilatory acclimatization to hypoxia in transgenic mice. Here we propose to test the hypothesis that both inflammatory signals and HIF-1? are necessary for plasticity in the control of breathing with chronic sustained hypoxia. In three specific aims, we will test the hypotheses that chemoreflex plasticity with chronic hypoxia requires (1) activation of NF-?B and HIF-1? in brainstem respiratory centers, (2) carotid body chemoreceptor afferent activation of microglia followed by astroglia activation that sustains an inflammatory and HIF-1? response, and (3) other isoforms of HIF in the brainstem are not necessary because reactive oxygen species (ROS) are not changing there with chronic hypoxia, although HIF-2? can affect the stability of breathing. Answering such questions could be important for common clinical scenarios where hypoxia and inflammation occur together, for example in COPD exacerbations or weaning from mechanical ventilation after sepsis in the ICU.